Non-insulin dependent diabetes mellitus (NIDDM) is a syndrome characterized by defects in insulin secretion and/or insulin action. Both genetic and nongenetic factors contribute to the development of this genetically heterogenous disorder. The past two years have seen great progress in our understanding of the molecular genetics of maturity-onset diabetes of the young (MODY), a form of NIDDM distinguished by onset usually before age of 25 years and an autosomal dominant mode of inheritance. However, there has been little progress in identifying the genes responsible for the common late-onset NIDDM which affects more than 95% of all subjects with this form of diabetes. Studies of "candidate genes" have contributed relatively little to our understanding of the susceptibility genes involved in the development of late-onset NIDDM and we do not know either how many such genes may be involved, their identities, mode of inheritance or how they may interact among themselves and with environmental factors to cause late onset NIDDM. Because of this uncertainty, it is our intention to systematically screen the human genome for late-onset NIDDM-susceptibility genes using DNA markers separated by 10 cM. Since the volume of work involved in such an endeavor is beyond the scope of a single research grant, four principal investigators (myself and Drs. Graeme Bell, Craig Hanis, and Richard Spielman) have submitted separate but related proposals for funding. Each PI (Concannon, Bell, Hanis and Spielman) will use the same set of DNA samples obtained from patients with late-onset NIDDM to systematically screen different regions of the genome for "genes responsible for NIDDM". The four PIs will share all resources (DNA samples from the families, oligonucleotide primers, etc.) and genotype data. Data management and linkage analyses will be performed on all samples at two of the centers (University of Chicago and University of Texas Health Science Center at Houston). This will allow uniform analyses to be performed on all the markers typed by each group including conditional analyses. The latter approach takes into account data at other loci such as those for candidate genes (e.g., insulin, insulin receptor and glucokinase genes) when analyzing data on specific markers. The advantage of the proposed collaborative approach is that it will allow the entire genome to be screened for susceptibility genes efficiently and rapidly. It is important to stress that the entire genome will be screened for NIDDM-susceptibility genes. The linkage studies will not be discontinued to concentrate on the cloning susceptibility loci once they have been identified. ALL the regions in the genome that contribute to NIDDM susceptibility will be identified. It is anticipated that the identification of the genes that contribute to the development of NIDDM will lead to a better understanding of the molecular basis of this disorder. The results of the study will also enable the identification of at-risk subjects before the onset of clinical disease as well as lead to the development of new treatment strategies based upon an understanding of the underlying molecular defects.